Physiology of Hypothalamic Neurosteroidal Progesterone

描述（由申请人提供）：神经类固醇，在大脑中合成的类固醇，涉及从压力，抑郁，焦虑到认知等功能。黄体酮是一种神经类固醇，它是一种典型的性激素，与生殖调节有关。虽然中枢神经系统有能力合成黄体酮，但迄今为止，似乎只有来自卵巢和肾上腺的外周黄体酮调节生殖。我们的初步研究表明，雌激素诱导的下丘脑黄体酮合成足以启动排卵和交配所需的生殖事件。卵巢切除和肾上腺切除（ovx/adx）大鼠的雌激素刺激增加下丘脑黄体酮水平。在这些动物中，雌激素诱导的前凸行为和黄体酮依赖的感知行为。同样，ovx/adx大鼠的雌激素刺激诱导黄体生成素（LH）激增。在这些大鼠中，阻断3β -羟基类固醇脱氢酶（3β - hsd），即将孕烯醇酮转化为孕酮的酶，可以防止黄体生成素激增。雌激素刺激培养的星形胶质细胞合成孕酮，提示胶质细胞可能介导雌激素正反馈。这些数据表明，在没有外周体源性组织的情况下，雌激素可以通过刺激神经甾体黄体酮的合成来诱导黄体酮依赖事件。我们建议验证这一假设：雌激素刺激下丘脑黄体酮的合成，激活调节黄体生成素激增和性行为的回路。我们提出了三个实验：首先，使用完整和ovx/adx大鼠模型，我们将直接测试雌激素诱导的LH激增是否依赖于下丘脑神经甾体孕酮的增加。其次，我们打算在体内和体外确定雌激素是否会增加合成孕酮所需的甾体生成酶（P450侧链裂解酶和3β - hsd）的表达和/或活性。第三，使用相同的完整和ovx/adx大鼠模型，我们将确定雌激素诱导的下丘脑黄体酮是否足以促进性行为。这些研究将进一步阐明黄体酮的生理作用，并为研究雌激素正反馈在中枢神经系统中的作用机制提供重要的新信息。

DESCRIPTION (provided by applicant): Neurosteroids, steroids synthesized in the brain, have been implicated in functions ranging from stress, depression, anxiety, to cognition. One neurosteroid is progesterone, a classic sex hormone involved in the regulation of reproduction. Although the CNS has the capacity to synthesize progesterone, to date it has appeared that only peripheral progesterone, from the ovaries and adrenals, regulates reproduction. Our preliminary studies have demonstrated that estrogen-induced hypothalamic progesterone synthesis is sufficient to initiate reproductive events necessary for ovulation and copulation. Estrogen stimulation of ovariectomized and adrenalectomized (ovx/adx) rats increased hypothalamic progesterone levels. In such animals, estrogen induced lordosis behavior and progesterone dependent proceptive behavior. Similarly, estrogen stimulation of ovx/adx rats induced a luteinizing hormone (LH) surge. In these rats, blocking 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the enzyme that converts pregnenolone to progesterone, prevented the LH surge. Estrogen stimulates astrocytes in culture to synthesize progesterone, suggesting that glial cells may mediate estrogen-positive feedback. These data indicate that, absent the peripheral steroidogenic tissues, estrogen can induce progesterone dependent events by stimulating the synthesis of neurosteroidal progesterone. We propose to test the hypothesis: estrogen stimulates synthesis of hypothalamic progesterone that activates circuits regulating the LH surge and sexual behavior. Three experiments are proposed: First, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependent on increased hypothalamic neurosteroidal progesterone. Second, we propose to determine whether estrogen increases the expression and/or activity of steroidogenic enzymes (P450 side chain cleavage and 3beta-HSD) needed to synthesize progesterone, in vitro and in vivo. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen-induced hypothalamic progesterone is sufficient to facilitate sexual behavior. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS.